The long-term objectives of this translational project is to optimize the use of the opioid antagonist naltrexone (NTX) for treating alcohol dependence and to identify novel receptor targets for new pharmacotherapies for alcohol drinking - a priority of NIAAA. The specific objective is to bring together experts to determine if Kappa opioid receptors (KOR) are affected by heavy drinking and if they have a role in mediating variability in efficacy of NTX. Knowledge gap: We need to know more about alcoholism, KOR, and how NTX decreases alcohol intake. Intriguing evidence from our group with an alcohol drinking paradigm (ADP) suggests that family history (FH) of alcoholism and gender may mediate responses to NTX. NTX decreased drinking in those with a positive FH (FHP) of alcoholism but appeared to increase drinking in negative FH (FHN) - a difference observed in male but not female drinkers. NTX binds with varying degrees to Mu, Delta and Kappa receptors. A prior PET study measured occupancy (OCC) of Mu and Delta sites by NTX but did not examine KOR, nor correlate with NTX efficacy. Another study compared baseline Mu and Delta sites in heavy drinkers (HD) to healthy controls (HC). PET imaging of KOR has been impossible due to the lack of a specific KOR tracer. Innovation: We have developed a selective KOR tracer. The current proposal will be the first to use this tracer to (1) image available KOR in HD at baseline, (2) to compare HD at baseline to HC, and (3) to compare OCC of KOR by NTX, in male and female, FHP and FHN HD. Our preliminary PET evidence suggests gender differences in baseline KOR levels in HC. It also suggests that FHP and FHN drinkers differ in NTX OCC of KOR and this may be associated with NTX-induced changes in drinking. Our new data suggest that KOR are higher in HD than HC. This would be counter to the recent findings regarding the Mu site. Our project will be the first to examine the association of KOR OCC by NTX with NTX- induced changes in drinking in the ADP, in male and female heavy drinkers who are either FHP or FHN. The primary hypothesis is that NTX OCC will be different in FHP vs. FHN HD and that such differences will predict NTX efficacy. We will use a novel tracer to shed light on possible effects of heavy drinking, the actions of NTX, and FH and gender-related differences. The work will inform future studies into the KOR/dynorphin system and the search for pharmacotherapies for alcoholism.